There is a growing need for making specific functionalization of various macromolecular systems (in short macromolecules) including large biomolecules and polymeric materials. A primary amine is a very versatile functional group, which can be used both a starting point for various chemical reactions and for modifying the physiochemical properties of the macromolecular system.
For many applications, it is furthermore required to have the functional group attached to the macromolecular system via a long chemical spacer arm in order to ensure optimal access to the functional group. Poly- or oligo-alkylene oxides represent a family of molecular fragments that can be used for such functional arms, while exhibiting a high compatibility towards biological or chemical environments depending on the application.
The macromolecular systems where such molecular entities are useful for forming amine functionalized products include biological molecules such as proteins and nucleotides, beaded materials for peptide synthesis, resins for chromatography, polymeric materials for filtration, as well as surface layers for use in medicinal components, in vivo or in vitro diagnostic components, analytical systems, etc.
In the literature, there are a number of methods for introducing primary amines as functional groups on polymer resins used for applications such as solid phase synthesis or chromatography. Most of these methods attach the amine group on the polymer backbone either directly or via a short (less than 10 atom) linker. Examples of that is the direct reaction of a deprotonated phthalimide with a primary alkyl halide followed by hydrazinolysis of the imide, and the reaction of azide with alkyl halides or tosylates followed by reduction. Also the reaction of bromoethyl phthalimide with alkoxide moieties on the macromolecule followed by hydrazinolysis has proven useful in some cases. In some cases, the primary amine functionality has been obtained as a terminal functional group on a long alkoxide spacer arm attached to a polymer resin. In these cases, the primary amine—alkoxide spacer arm moiety is formed in a stepwise fashion i.e. the alkoxide spacer arm is attached followed by the attachment of the primary amine to the alkoxide spacer arm using reactions as described above. The chemistry involved in the methods described above requires quite harsh conditions which often are incompatible with the macromolecular systems. Especially biological macromolecules are degraded, but also resins used for chromatography can be harmed under such conditions. In the later case this is especially important for macroporous resins where the harsh condition will alter the porosity of the resins. In addition, the mentioned reactions rarely are quantitative, which give rise to undesired side products.
Examples of unsymmetrical alkylene oxides prepared from ethylene glycol in which one terminal group is an amine and one terminal group is a hydroxide do exist. These compounds mainly exist as short oligomeric versions where the separation from the symmetrical alkylene oxides is possible. Moreover, the high cost of producing these molecules and the difficulty in selectively converting the hydroxy functionality into a reactive group that can be reacted with a macromolecular system strongly limit the industrial applicability of these compounds for the functionalization of macromolecular systems.
Examples of unsymmetrical peg prepared by direct ethoxylation of an ethanolamine with a amide or imide protection group have been described in the literature.
Lange and Wahl (Bull. Chim. Soc. Fr. 1951, 340-342) described the ethoxylation of N-acetylethanoamine forming mono and diethoxylated derivatives. Lontjens et al. (Polym. Bull. 30, 1993 pp. 489-494) describe the synthesis of monoamino polyethylene glycols in a high temperature ethoxylation process, which does create a number of by-products. Y-I Huang (J. polym. Sci. 23, 1985, pp. 795-799) describe the ethoxylation of an ethanolamine-benzaldehyde Shiff-base followed by hydrolysis to the monoamine-substituted polyethylene glycol. In these last two examples, the product was reacted via the primary amine primary amine to form the polymeric entities leaving a free hydroxyl group. In no case, a primary amine derivative was obtained.
Thus, there is a need in the art for molecular entities, which allow the efficient and inexpensive functionalization of macromolecular systems with an alkoxide spacer arm and a primary amine functionality.